PROJECT SUMMARY/ABSTRACT Over the past couple of decades, we have learned a great deal about the mechanisms of Alzheimer?s disease (AD) pathogenesis, but many critical questions remain unanswered. As the recent failures of clinical trials in AD have raised questions as to the amyloid hypothesis validity, the ?neuroinflammation hypothesis? begins to gain attention to explain AD pathogenesis. While ?the interactions between central and peripheral immunity? elevate inflammatory impact on the AD pathogenesis, the mechanism involved remains poorly understood. This is due, in large part, to limited information on the various risk factors associated with AD onsets and its progression; the dynamic and multiple functional phenotypes exhibited by immune cells depending on their activation status and the extracellular milieu; orchestral interactions among multiple cells types; and especially the lack of relevant human AD models. The goals of this project are to develop biomimetic ?human glia- vascular-leukocyte axis in AD? that faithfully reproduce key aspects of AD pathology, such as amyloid beta accumulation, phosphorylated tau aggregates, and neurotoxic proinflammation as a reductive, but controlled way and begin to evaluate the interplay between microglia and neutrophil remodeling environments with stimuli of AD cues. To achieve these goals, we have the following specific aims: Aim 1) To develop a human AD brain model and evaluate neuroinflammatory responses to AD cues; Aim 2) To create a human BBB model to evaluate disrupted BBB integrity by neuroinflammatory stimuli; and Aim 3) To construct a ?human glia-vascular-leukocyte axis in AD? model to assess the roles of central-peripheral immunity in AD pathogenesis. Taken together, the application of micro-scaled technologies and quantitative analysis tools to create cellular models of human AD brains will allow us to explore the pathways underlying AD pathology and are expected to identify new points for therapeutic intervention in the treatment of the disease. This integrative project offers tremendous opportunities for hands-on laboratory experiences for both undergraduate and graduate students in engineering and biological sciences as it strengthens Biomedical Engineering research and practice at the University of North Carolina at Charlotte.